Evidence map›Paper›PMID 37156295›Full record

ArticleFree radical biology & medicine2023

Structural and biochemical characterization establishes a detailed understanding of KEAP1-CUL3 complex assembly.

Roslin J Adamson, N Connor Payne, Sergio G Bartual, Ralph Mazitschek, Alex N Bullock

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PubMed Full text at PMC Publisher
In one paragraph

Article in Free radical biology & medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.

0numbers the graph read from it
0cells of the map it votes in
13citing papers in PubMed
4.2field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

13 citing papers in PubMed, 27 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors at 3 institutions in 2 countries.

Roslin J AdamsonCentre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK.
N Connor PayneCenter for Systems Biology, Massachusetts General Hospital, Boston, MA, 02114, USA; Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.
Sergio G BartualCentre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK.
Ralph MazitschekCenter for Systems Biology, Massachusetts General Hospital, Boston, MA, 02114, USA; Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. Electronic address: ralph@broadinstitute.org.
Alex N BullockCentre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK. Electronic address: alex.bullock@cmd.ox.ac.uk.
University of Oxford · GBBroad Institute · USHarvard University · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

KEAP1 promotes the ubiquitin-dependent degradation of NRF2 by assembling into a CUL3-dependent ubiquitin ligase complex. Oxidative and electrophilic stress inhibit KEAP1 allowing NRF2 to accumulate for the transactivation of stress response genes. To date there are no structures of the KEAP1-CUL3 interaction nor binding data to show the contributions of different domains to their binding affinity. We determined a crystal structure of the BTB and 3-box domains of human KEAP1 in complex with the CUL3 N-terminal domain that showed a heterotetrameric assembly with 2:2 stoichiometry. To support the structural data, we developed a versatile TR-FRET-based assay system to profile the binding of BTB-domain-containing proteins to CUL3 and determine the contribution of distinct protein features, revealing the importance of the CUL3 N-terminal extension for high affinity binding. We further provide direct evidence that the investigational drug CDDO does not disrupt the KEAP1-CUL3 interaction, even at high concentrations, but reduces the affinity of KEAP1-CUL3 binding. The TR-FRET-based assay system offers a generalizable platform for profiling this protein class and may form a suitable screening platform for ligands that disrupt these interactions by targeting the BTB or 3-box domains to block E3 ligase function.

Indexed as

Cullin ProteinsNF-E2-Related Factor 2HumansKelch-Like ECH-Associated Protein 1Protein BindingUbiquitinUbiquitin-Protein LigasesCUL3 protein, humanCullin ProteinsKEAP1 protein, humanKelch-Like ECH-Associated Protein 1NF-E2-Related Factor 2UbiquitinUbiquitin-Protein LigasesBTBCullin-RING ligaseKEAP1KelchTR-FRETUbiquitin

Identifiers

PMID37156295
PMCPMC10564622
OpenAlexW4372344097

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.